Recently, thromboembolic disorders, such as myocardial infarction, cerebral thrombosis and peripheral arteriothrombosis, are increasing year by year with the popularization of Western life-styles and the increase in aged population, and there is much increasing social demand for the treatment of such disorders.
Anticoagulant therapy as well as adenolytic therapy and antiplatelet therapy is a part of medical therapy for treatment and prevention of thrombosis (Sogo Rinsho, 41: 2141-2145, 1989). In particular, anticoagulants for prevention of thrombosis indispensably require high safety for long-term administration and the ability of surely and appropriately expressing the anticoagulation activity.
However, the anticoagulating ability of warfarin potassium, which is only one oral anticoagulant now being popularly used in the world, is difficult to control because of the characteristic of itself based on the action and the mechanism thereof (J. Clinical Pharmacology, 32, 196-209, 1992; and N. Eng. J. Med., 324 (26), 1865-1875, 1991), and the drug is extremely difficult to use in clinics.
It is known that thrombin acts to convert fibrinogen into fibrin in the final stage of coagulation, while deeply participating in the activation and the coagulation of platelets. At present, however, no oral thrombin inhibitor is commercially available because of its low bioavailability in oral administration and of its low safety (Biomed. Biochim. Acta, 44, 1201-1210, 1985).
On the other hand, the activated blood coagulation factor X is a key enzyme existing in the junction of intrinsic and extrinsic coagulation cascade reactions, and inhibiting this factor is more efficient than thrombin inhibition, and could bring about specific inhibition of coagulation systems (THROMBOSIS RESEARCH (19), 339-349, 1980).
As compounds having the ability of inhibiting the activated blood coagulation factor X, known are amidinonaphthylbenzene derivatives or their salts (JP-A-5-208946; Thrombosis Haemostasis, 71 (3), 314-319, 1994; Thrombosis Haemostasis, 72 (3), 393-396, 1994); and WO96/16940 discloses amidinonaphthyl derivatives of the following general formula or their salts. ##STR2##
[In the formula, B represents a lower alkylene group, etc.; R.sup.1 represents a hydrogen atom or a group of a formula, --A--W--R.sup.4 [where A represents --CO--, --SO.sub.2 --, etc.; W represents a single bond or an --NR.sup.5 -- group (where R.sup.5 represents a hydrogen atom, a --CONH.sub.3 group, etc.); R.sup.4 represents an optionally-substituted lower alkyl group, etc.]; R.sup.2 represents a lower alkyl group; R.sup.3 represents a hydrogen atom, a halogen atom, etc.; and n=0 or 1.]
As so mentioned above, inhibitors for the activated blood coagulation factor X are more effective than thrombin inhibitors in anticoagulant therapy, and are expected to bring about specific inhibition of coagulation systems.
Accordingly, it is desired to create selective activated blood coagulation factor X inhibitors, which are different from the known compounds noted above in the chemical structure, can be orally administered and are more effective.